The isolated perfused rat liver is being used to study the regulation of hepatic HMG CoA reductase. To date, it has been found that pure cholesterol but not bile salts can alter the activity of the enzyme in this system. Moreover, it has been found that although 7 ketocholesterol does suppress the activity of this enzyme acutely, the liver possesses a pathway which rapidly converts this sterol to bile salts, and escape from control by this sterol occurs, making it unlikely that this sterol is a physiologic regulator of hepatic sterol synthesis. The ability of lipoproteins to serve as regulators has also been assessed. It is found that whole chylomicrons are not removed by the liver and therefore do not alter hepatic cholesterol synthesis, but that preincubation with post heparin plasma creates "remnants" which are removed by liver and do suppress hepatic cholesterol synthesis.